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Figure S3 from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer

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posted on 2023-03-31, 06:03 authored by Li-Li Long, Si-Cong Ma, Ze-Qin Guo, Yan-Pei Zhang, Zhenzhen Fan, Li-Juan Liu, Li Liu, Duan-Duan Han, Meng-Xin Leng, Jian Wang, Xue-Jun Guo, Jia-Le Tan, Xiao-Ting Cai, Yan Lin, Xinghua Pan, De-Hua Wu, Xue Bai, Zhong-Yi Dong

Overexpression of mutant PARP1 promotes activation of the IFNγ signaling pathway. (a, b) A549 lung cancer cells and LLC1 lung cancer cells were transfected with the catalytic mutant Flag-PARP1 (E988) followed by stimulation with IFNγ. The lysates were then subjected to western blot analysis for indicated proteins.

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National Natural Science Foundation of China (NSFC)

Young Scientists Fund

Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University

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ARTICLE ABSTRACT

Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

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